This research proposal will continue to focus on a systematic study of the physiological and physiopathological relationships between the two major endocrine systems that control adrenal and gonadal function. The project will study the role of the hypothalamic-pituitary-adrenal axis and of the hypothalamic neuropeptides that control it in the physiology of the menstrual cycle and in the etiology of the hypothalamic amenorrhea or anovulatory syndrome. The studies will be performed in the female rhesus monkey, an animal model chosen specifically for its similarity with the human in terms of the menstrual cycle and reproductive function. Presently, we have demonstrated a direct causal inhibitory action of CRH, the principal neuropeptide in control of adrenal function, on LH and FSH secretion in the ovariectomized (OVX) monkey.
In aim 1, we will investigate whether other neuropeptides which are released within the hypothalamus by stress or immune challenge, for ex. vasopressin, also exert such an inhibitory influence on gonadotropin release in the OVX monkey.
In aim 2, we will study whether and how ovarian steroid replacement therapy in the OVX monkey modulate these adrenal-gonadal axes relationships. Such ovarian steroid modulation, of course, would bear major consequences in regard to the physiopathological relationships between these two endocrine axes during the normal menstrual cycle, as studied in aim 3. The objective of this aim in the intact animal will be to determine both how the adrenal axis, in a """"""""permissive"""""""" role may promote specific events so that the ovulatory cycle is facilitated, and how subtle abnormalities of the hypothalamopituitary-adrenal axis can """"""""inhibit"""""""" or interfere with the normal sequence of events that characterize the ovulatory menstrual cycle.
Aim 4 will study the role of adrenal axis neuropeptides in the pathology of the menstrual cycle, as exemplified in the hypothalamic amenorrhea syndrome. Overall, these studies will shed light on the processes whereby activation of the adrenal axis, such as that which occurs in 'stress', interferes with normal reproductive function and on the mechanisms whereby the adrenal axis may act in support of normal cyclic function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK039144-07
Application #
3238859
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1987-09-01
Project End
1996-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas et al. (2007) Astressin B, a corticotropin-releasing hormone receptor antagonist, accelerates the return to normal luteal function after an inflammatory-like stress challenge in the rhesus monkey. Endocrinology 148:841-8
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2005) Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology 146:784-9
Vulliemoz, Nicolas R; Xiao, Ennian; Xia-Zhang, Linna et al. (2004) Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 89:5718-23
Xiao, Ennian; Xia-Zhang, Linna; Vulliemoz, Nicolas R et al. (2003) Leptin modulates inflammatory cytokine and neuroendocrine responses to endotoxin in the primate. Endocrinology 144:4350-3
Xiao, Ennian; Xia-Zhang, Linna; Ferin, Michel (2002) Inadequate luteal function is the initial clinical cyclic defect in a 12-day stress model that includes a psychogenic component in the Rhesus monkey. J Clin Endocrinol Metab 87:2232-7
Zimmermann, R C; Xiao, E; Husami, N et al. (2001) Short-term administration of antivascular endothelial growth factor antibody in the late follicular phase delays follicular development in the rhesus monkey. J Clin Endocrinol Metab 86:768-72
Xiao, E; Xia-Zhang, L; Ferin, M (2000) Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist. Neuroimmunomodulation 7:15-Jun
Xiao, E; Xia-Zhang, L; Ferin, M (1999) Stress and the menstrual cycle: short- and long-term response to a five-day endotoxin challenge during the luteal phase in the rhesus monkey. J Clin Endocrinol Metab 84:623-6
Xiao, E; Xia-Zhang, L; Barth, A et al. (1998) Stress and the menstrual cycle: relevance of cycle quality in the short- and long-term response to a 5-day endotoxin challenge during the follicular phase in the rhesus monkey. J Clin Endocrinol Metab 83:2454-60
Xiao, E; Xia-Zhang, L; Shanen, D et al. (1997) Tonic support of luteinizing hormone secretion by adrenal progesterone in the ovariectomized monkey replaced with midfollicular phase levels of estradiol. J Clin Endocrinol Metab 82:2233-8

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